One of the major morbidity and mortality factors confronted by diabetic patients is an increased risk of developing diabetic nephropathy that often progresses to End-Stage Renal Disease (ESRD) (US Renal Data System: Excerpts from the USRDS 2000 Annual Data Report: Atlas of End-Stage Renal Disease in the United States, Am. J. Kidney Dis. 36:S1-S238, 2000; Parving, H. H., et al., “Diabetic Nephropathy,” In Brenner and Rector's The Kidney 6th Edition, W. B. Saunders Company, pp. 1731-1773, 2000; Viberti, G., et al., Joslin's Diabetes, pp. 691-737, 1992). A long-standing question pertaining to the development of renal disease in diabetes concerns the mechanisms involved in this process. A wealth of data has been generated on possible mechanisms by which diabetes and its ancillary metabolic, hemodynamic, glomerular growth and glomerular cell injury-related alterations may modulate the progression of diabetic nephropathy (Viberti, G., Kidney Internat. 55(6):2526-2527, 1999; Sullivan, J. L., Circulation 100(12):1260-1263, 1999; Orloff, L. A., et al., Arch. Surg. 134(8):889-897, 1999; Lewis, J. and Lewis, E. J., Sem. Nephrol. 21(2):124-132, 2001). Nevertheless, the observation that approximately ⅔ of diabetic patients do not develop renal disease indicates that hyperglycemia is a permissive factor in diabetic nephropathy and elevated plasma glucose levels alone do not fully account for renal injury (US Renal Data System: Excerpts from the USRDS 2000 Annual Data Report: Atlas of End-Stage Renal Disease in the United States, Am. J. Kidney Dis. 36:S1-S238, 2000). Thus, genetic factors are thought to play a major role in the susceptibility for diabetic nephropathy and there are several clinical and epidemiological studies that strongly support this view (Seaquist, E. R., et al., New Eng. J. Med. 320:1161-1165, 1989; Freedman, B. I., et al., Am. J. Kidney Dis. 25(5):710-713, 1995).
The complex interplay between diabetes-dependent and independent factors in determining the progression of renal disease could become more amenable to study if there were an adequate animal model which spontaneously develops diabetes and renal lesions that mimic those seen in patients with diabetic nephropathy. However, to date, no rodent model of diabetes has been developed that fully recapitulates the chronology of events and histologic changes in the kidney that are characteristic of patients with diabetic nephropathy. The lack of suitable small animal models for diabetic nephropathy is severely hindering efforts to identify biological markers predictive of diabetes-related ESRD and in the development of new drug treatments that might slow the progression of diabetic nephropathy.
Several rodent models of spontaneous diabetes (Zucker, BB rat, DB mice) exist that exhibit thickening of basement membranes and mild diffuse focal glomerulosclerosis (Marliss, E. B., et al., Metabolism 32(Supp. 1):1989; Schmitz, P. G., et al., Am. J. Physiol. 263(32):F496-F502, 1992; Valesquez, M. T., et al., Diabetologia 38:31-38, 1995) that resemble some of the changes seen in the kidneys of patients with diabetes. However, these models, unlike human diabetic nephropathy, do not exhibit glomerular hypertrophy, expansion of mesangial matrix leading first to focal glomerular sclerosis and proteinuria and later progressing to the development of severe global glomerulosclerosis and proteinuria with nodule formation (Kimmelstiel-Wilson lesions) followed by end stage renal disease characterized by elevations in blood urea nitrogen level and plasma creatinine concentration followed by death.
It is well recognized that strain differences may account for differences in the severity of diabetes-associated renal injury in some mouse models (Zheng, F., et al., Kidney Inter. 54:1999-2007, 1998). Thus, it is possible that there may be factors that predispose certain strains of rats and mice to develop diabetic nephropathy that have not yet been characterized since they exist in a genetic background which does not develop diabetes.
One such strain of a spontaneously diabetic rat that may harbor genetic factors predisposing them to renal disease is the GK rat. This strain is a non-obese, normotensive model of non-insulin-dependent diabetes mellitus (NIDDM). GK rats display glucose intolerance as early as two weeks of age (high basal serum insulin levels) and exhibit elevated plasma glucose levels following administration of a glucose load by four weeks of age (Portha, B., et al., Diabetes 40:486-491, 1991; Ostenson, C. G., et al., Diabetologia 36:3-8, 1993; Guenifi, A., et al., Pancreas 10:148-153, 1995). By 12 weeks of age, GK rats exhibit frank Type II diabetes characterized by elevated by fasting glucose and insulin levels and a prolonged elevation in plasma glucose levels following an oral glucose load. Several investigators have reported that GK rats exhibit some of the common histological changes in the kidney seen in most animal models of diabetes, including thickening of the glomerular basement membranes, mild expansion of the mesangial matrix, glomerular hypertrophy and mild diffuse focal glomerulosclerosis (Yagihashi, S., et al., Diabetologia 15:309-312, 1978; Phillips, A. O., J. Am. Soc. Nephrol. 9:639A, 1998). Nevertheless, extensive follow-up studies of GK rats indicate that even very old GK rats do not exhibit progressive renal disease characterized by the development of severe global glomerulosclerosis and nodule formation, marked proteinuria, and end stage renal disease (elevated BUN and plasma creatinine concentration) (Phillips, A. O., et al., Am. J. Kidney Dis. 37(2):400-410, 2001; Riley, S. G., et al., J. Labor. Clin. Med. 134(3):304-312, 1999).
An improved animal model of diabetic nephropathy is sorely needed to study the genetic basis of diabetic nephropathy, to identify new biomarkers and diagnostic tests for susceptibility to develop diabetes-related disorders and to develop new drugs and genetic therapies (siRNA, oligonucleotides, viral constructs, and/or antibody therapies) that might alter the progression of diabetes or diabetic nephropathy.